There is a steadily growing need for effective treatment of neurological dysfunction which produces cognitive and neurological deficiencies. Many of these diseases are caused by degenerative changes in the nervous system. Typically, the incidence of these diseases increases as a function of age. Deficits in the synthesis and release of acetylcholine in the brain are generally thought to be related to cognitive impairment (see Francis et al., New England J. Med.. 313, 7, 1985), whereas neurological deficits (e.g., Parkinsonian symptoms) and mood/mental changes may be related to impairment of d.opaminergic and serotonergic systems, respectively. Other neurological deficits (e.g., myasthenia gravis) are related to cholinergic deficiencies in the peripheral nervous system.
Treatment strategies employed hitherto encompass vasoactive drugs like vincamine and pentoxifylline; "metabolic enhancers" like ergoloid mesylates, piracetam and naftidrofuryl; neurotransmitter precursors like 1-DOPA, choline and 5-hydroxytryptamine (5HT); transmitter metabolizing enzyme inhibitors like physostigmine (PH); and neuropeptides like adrenocorticotropic hormone and vasopressin-related peptides. These treatment strategies generally have failed to produce clinically significant improvements (Hollister et al., Drugs, 29, 483, 1985) similar to the improvements obtained by treating Parkinson's disease with 1-dopa or treating myasthenia gravis with cholinesterase inhibitor. Enhancement of the residual function of the affected systems by enhancing the stimulus-induced release of neurotransmitters provides an alternative to treat these multiple symptoms. Theoretically, such an enhancement would improve the signal-to-noise ratio during chemical transmission of information, thereby reducing deficits in processes related to cognition, neurological function, and mood regulation.
Recent findings suggest that the cerebral cholinergic system may be involved in the senile decline of cerebral function. Cortical acetylcholine (ACh) synthesis and release decline as a function of age in experimental animals as described by (Gibson et al., J. Neurochem., 38, 488, 1982). The primary deficit in patients suffering from Alzheimer's disease is one of cholinergic origin. There is a marked reduction in the number of cholinergic cell bodies in the nucleus basalis of Meynert resulting in a decrease of choline acetyltransferase activity, acetylcholinesterase activity, and acetylcholine synthesis in the cortical and hippocampal projection areas as described by (Perry et al., J. Neuro., 40, 503, 1983). Furthermore, the noradrenergic, the dopaminergic, and the serotonergic systems also appear to be deficient in a majority of patients suffering from Alzheimer's disease (Davis et al., Physchopharm, Bulletin, 19, 451, 1983).
Researchers have attempted to enhance the neuronal function by using drugs which enhance endogenous stimulus-induced neurotransmitter release which would result in an increase of the amount of neutrotransmitter solely when its release is triggered by excitation of the cholinergic neuron. Such action should result in an improvement of the signal-to-noise ratio during transmission in the cholinergic function without the ACh overload toxicity that is typical for cholinesterase inhibitors, or without the distortion of temporal patterns in cholinergic transmission, as caused by direct cholinergic agonists.
Cognitive deficits resulting from neuropathological brain changes or normal aging are most likely due to alterations in multiple neurotransmitter systems. Cholinergic, noradrenergic, dopaminergic, and peptidergic neurotransmitter systems have all been implicated in the mediation of learning and memory decline associated with aging (e.g., Olton et al., Ann, New York Acad. Sci., 444, 1985; Moos et al., Med. Res. Rev., 8, 353-392, 1988). A majority of research has focused on the cholinergic nervous system with particular reference to cognitive deficits resulting from Alzheimer's disease (AD).
As a result a number of drugs that increased brain cholinergic activity have been used clinically to treat various neurological disorders resulting in cognitive impairment (Moos et al., Med. Res. Rev., 8, 353-392, 1988). Attempts to increase acetylcholine (ACh) synthesis by treatment with ACh precursor choline or lecithin have not been very successful. More recent research focused upon the use of muscarinic agonists, or cholinesterase inhibitors (AChE) such as physostigmine (PH) and tetrahydroacridine (THA), both of which increase ACh by inhibiting its metabolic degradation after release. Recent reports of limited success in reducing the cognitive deficits and symptoms of dementia in AD by treatment with AChE inhibitors such as PH (Davis et al., N. Eng. J. Med., 301, 946, 1979) and THA (Summers et al., N. Eng. J. Med., 315, 1241-1245, 1986) have renewed interest in the search for other cholinomimetic agents that have similar mechanisms of action. However, the potential therapeutic application of AChE inhibitors is limited by several factors. The most predominant one being side effects resulting from chronic post-synaptic stimulation.
As an alternative to inhibiting the AChE activity resulting in increased ACh with abnormal enzymatic degeneration, a search was undertaken to identify ACh release enhancers. Compounds which can be used to enhance the neuronal function are disclosed in U.S. Pat. No. 4,760,083, issued to Myers et al. on July 26, 1988, U.S. Pat. No. 4,876,259, issued to Myers et al. on Oct. 24, 1989, and in coassigned application Ser. No. 07/234,382, filed Aug. 23, 1988 (European Patent Application Publication No. 0311010, published Apr. 12, 1989). 3,3-Disubstituted indolines are described which enhance stimulus-induced release of neurotransmitters, specifically acetylcholine, as well as, dopamine and serotonin. These compounds were screened for this activity by evaluating their effect on the release of a neurotransmitter, such as acetylcholine (ACh), from rat cerebral cortex slices using a superfusion procedure described by Mulder et al., Brain Res., 70, 372, 1974, as modified according to Nickolson et al., Naunyn Schmied. Arch. Pharmacol., 319, 48, 1982.
Compounds with such activity can be useful in treating cognitive and/or neurological deficiencies and/or mood or mental disturbances such as found in patients suffering from degenerative nervous system disorders, for example, Alzheimer's disease, Parkinson's disease, senile-dementia, multi-infarct dementia, Huntington's disease, mental retardation, and myasthenia gravis.
The compounds disclosed in U.S. Pat. Nos. 4,760,083 and 4,876,259, include 3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one (DuP 996), which has been shown to enhance stimulated ACh release from rat cortical, hippocampal and striatal slices in vitro and from the cortex of awake freely moving rats in vivo without changes in AChE activity (Nickolson et al., Drug Develop, Research, 19/3, 285-300, 1990). In addition, previous studies have shown that DuP 996 protects against hypoxia-induced amnesia of a passive avoidance (PA) response in rats at a dose range of 0.01 to 0.1 mg/kg s.c. (Cook et al., Drug Develop, Research, 19, 301-314, 1990).
It appears that hypo-cholinergic function results in dementia, but dementia is not always due to a deficit in cholinergic transmission. It can be mediated by other neurotransmitter systems. It is well established that there is a decrease in forebrain 5-hydroxytryptamine (5HT) in the AD brain. Specifically, concentrations of 5HT and its metabolite 5-hydroxyindole acetic acid are reduced and the 5HTl- and 5HT.sub.2 -receptor densities decreased in hippocampus, frontal, and temporal cortices (e.g., Palmer et al., Ann. Neurol., 23, 616-620, 1988). However, the loss of serotonin innervation does not parallel the loss of cholinergic or adrenergic innervation (e.g., Davies et al., Lancet, 2, 1403, 1976; Adolfsson et al., Br. J. Psychiatry, 135, 216-223, 1979), and it may be hypothesized that the inhibitory tone that the serotonergic nervous system is suspected to have on other neurotransmitter systems would be maintained or even exaggerated (Normile et al., Plenum Pub. Coro., 141-156, 1987). In that regard, 5HT antagonists would be expected to improve performance by decreasing the inhibitory control maintained on the central nervous system.
A recent series of reports has shown that a number of 5HT receptor antagonists, both non-selective (e.g., metergoline), and 5HT2-receptor selective (e.g., pirenperone, ketanserin) can enhance memory of a previously learned inhibitory response in mice (e.g., Altman et al., Pharmacol. Biochem, Behav., 28, 353-359, 1987) and can reverse hypoxia-induced passive avoidance (PA) retention deficits in rats (e.g., Strek et al., Pharmacol, Biochem. Behav., 33, 241-244, 1989). These studies support the notion that 5HT antagonists administered after avoidance training or after an experimentally induced memory deficit (exposure to hypoxia) can enhance retrieval in mice (e.g., Altman et al., Pharmacol. Biochem. Behav., 28, 353-359, 1987) and protect rats from experimentally-induced amnesia (e.g., Strek et al., Pharmacol. Behav., 33, 241-244, 1989).
European Patent Application Publication No. 279,990, published on Aug. 31, 1988, describes the use of heterocyclic 5-hydroxytryptamine antagonists for treating cognitive disorders.